A new therapeutic strategy against hormone-dependent breast cancer: the preclinical development of a dual aromatase and sulfatase inhibitor.
OBJECTIVE
The production of E2 is paramount for the growth of estrogen receptor-positive breast cancer. Various strategies have been used, including the use of enzyme inhibitors against either aromatase (AROM) or steroid sulfatase (STS), in an attempt to ablate E2 levels. Both these enzymes play a critical role in the formation of estrogenic steroids and their inhibitors are now showing success in the clinic.


METHODS
We show here, in a xenograft nude mouse model, that the inhibition of both enzymes using STX681, a dual AROM and STS inhibitor (DASI), is a potential new therapeutic strategy against HDBC. MCF-7 cells stably expressing either AROM cDNA (MCF-7(AROM)) or STS cDNA (MCF-7(STS)) were generated. Ovariectomized MF-1 female nude mice receiving s.c. injections of either androstenedione (A(4)) or E2 sulfate and bearing either MCF-7(AROM) or MCF-7(STS) tumors were orally treated with STX64, letrozole, or STX681. Treatment was administered for 28 days. Mice were weighed and tumor measurements were taken weekly.


RESULTS
STX64, a potent STS inhibitor, completely blocked MCF-7(STS) tumor growth but failed to attenuate MCF-7(AROM) tumor growth. In contrast, letrozole inhibited MCF-7(AROM) tumors but had no effect on MCF-7(STS) tumors. STX681 completely inhibited the growth of both tumors. AROM and STS activity was also completely inhibited by STX681, which was accompanied by a significant reduction in plasma E2 levels.


CONCLUSIONS
This study indicates that targeting both the AROM and the STS enzyme with a DASI inhibits HDBC growth and is therefore a potentially novel treatment for this malignancy.
Foster
Paul A
PA
Faculty of Medicine, Imperial College London, UK. paul.foster@imperial.ac.uk
Chander
Surinder K
SK
Newman
Simon P
SP
Woo
L W Lawrence
LW
Sutcliffe
Oliver B
OB
Bubert
Christian
C
Zhou
Dujin
D
Chen
Shiuan
S
Potter
Barry V L
BV
Reed
Michael J
MJ
Purohit
Atul
A
D000284:Administration, Oral; D000818:Animals; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D001378:Azasteroids / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000601:surgery; D049109:Cell Proliferation / Q000187:drug effects; D004967:Estrogens / Q000097:blood; D005260:Female; D006801:Humans; D000077289:Letrozole; D051379:Mice; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy* / Q000201:enzymology / Q000601:surgery; D009570:Nitriles / Q000627:therapeutic use; D010052:Ovariectomy; D051381:Rats; D017208:Rats, Wistar; D043266:Steryl-Sulfatase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016896:Treatment Outcome; D014230:Triazoles / Q000627:therapeutic use; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
D047072:Aromatase Inhibitors; D001378:Azasteroids; D004967:Estrogens; D009570:Nitriles; C515227:STX 213; D014230:Triazoles; D000077289:Letrozole; D043266:Steryl-Sulfatase